Hydrogels and sponges are polymer networks characterised by a three-dimensional structure, which is compact in the case of hydrogels and has interconnected pores in the case of sponges. Sponges normally absorb a great deal of water, whereas this characteristic (“swelling”) may be less marked in hydrogels, depending on the compactness of the hydrogel; a very compact gel absorbs less water than one which is not very compact.
These types of materials have been studied for some time; for example, hydrogels are used in the fields of drug delivery, soft tissue filling, and joint disorders that benefit from the insertion into the joint of “bearings” that absorb tensions and shocks. Sponges are used in particular in the field of tissue engineering, especially for their ability to be colonised by cells. The applications obviously depend entirely on the nature of the starting polymer used. Specifically in the case of the present invention, the polymer chosen is a polysaccharide, namely hyaluronic acid (HA), a heteropolysaccharide consisting of alternating residues of D-glucuronic acid and N-acetyl-D-glucosamine. It is a linear-chain polymer with a molecular weight of up to 13×106 Da, depending on the source from which it is obtained and the preparation methods used. It is ubiquitously present and plays an important role in the biological organism, especially as a mechanical support for the cells of many tissues, such as skin, tendons, muscles and cartilage. It also modulates many different processes relating to cell physiology and biology, such as cell proliferation, migration and differentiation and angiogenesis (Weigel P. et al., J Theoretical Biol, 1986:219-234; Abatangelo G. et al., J Surg Res, 1983, 35:410-416; Goa K. et al., Drugs, 1994, 47:536-566), and also performs other functions, such as tissue hydration and joint lubrication. In the joints, the hyaluronic acid contained in the synovial fluid acts as a viscous lubricant during slow movements, while during fast movements, due to its elastic properties, it absorbs any traumas or microtraumas affecting the joint (Balazs EA. et al., J Rheumatol Suppl, 1993, 12:75-82; Belcher C. et al., Annals of the Rheumatic Diseases, 1997, 56:299-307). The combination of these properties, which are widely recognised, has been exploited for some time in the preparation of dressings used in the treatment of wounds, ulcers and skin lesions of various origins, and in medical devices designed for intra-articular application for the treatment of osteoarthritis, cartilage degeneration, etc.
Numerous methods are used to obtain hydrogels with specific characteristics from various polysaccharides; the most important used successfully on hyaluronic acid include chemical crosslinking, using molecules (divinyl sulphone, BDDE) that specifically react with given functional groups, or free-radical polymerisation. These methods, which presuppose a chemical modification of HA to make them suitable for the subsequent crosslinking or polymerisation (derivatisation) reaction, give rise to hydrogels with good characteristics of compactness, chemical and mechanical resistance and hydratability; however, as the derivatisation and crosslinking take place simultaneously, reagent residues can be retained in their structure during the formation of the gel, and are very often toxic because they are difficult to eliminate.
Another system for obtaining the formation of a polymer crosslink is the use of UV radiation on polysaccharides previously derivatised with suitable functional groups to render them photoreactive. Derivatisation involves bonding to the polysaccharide substances which, when activated by UV radiation, bond together, crosslinking the different polymer chains and thus creating the network. Said process is particularly advantageous because it allows easy, effective elimination of undesirable reaction residues or intermediates during the derivatisation step, and therefore helps to make the end product safer. Numerous photoreactive substances can be used; for example, both hydrogels (EP0554898; U.S. Pat. No. 6,602,859) and sponges (EP1666503) obtained from HA derivatised with cinnamic acid or thymine are known. In these cases, hyaluronic acid is bonded to the cinnamic acid or thymine residue and then irradiated to obtain the hydrogel; for sponges, the hydrogel is freeze-dried or frozen, and then undergoes a second irradiation cycle. A further photoreactive substance which can be used is propiophenone; gels obtained from hyaluronic acid or derivatives thereof which are bonded via ester bonds to propiophenone and then irradiated are known (EP1519962). Other photoreactives known in the prior art are anthracene, riboflavin, coumarin and uracil, suitably derivatised and substituted, to promote the bond with the polysaccharide, which is normally the ester or amide type and therefore involves the —OH, —COOH and —NH2 groups normally present in the polysaccharide. The polysaccharide is often derivatised before the reaction, for example to protect some functional groups or to promote the formation of the desired bond. The characteristics of hydrogels, such as compactness, hydratability, mechanical strength, etc., can be varied by modulating the various parameters (type of polysaccharide, photoreactive, bond between the two entities, percentage of photoreactive compared with polysaccharide, intensity and duration of irradiation).
In the ambit of the present invention the Applicant has surprisingly discovered that hyaluronic acid bonded to particular photoreactive via a specific spacer produces, after suitable UV irradiation, hydrogels of excellent compactness which are biodegradable, biocompatible, non-toxic and have shape memory properties; in other words said hydrogels maintain the shape of the container in which they were prepared, and can be cut while retaining their structure, or otherwise very easily manipulated. The same characteristics also belong to the sponges claimed herein, and are obtained innovatively not from a hydrogel, as described to date by the prior art, but from a solution of hyaluronic acid bonded to the spacer and the photoreactive, subsequent freeze-drying, and finally UV irradiation; unlike known sponges, only a single irradiation step is therefore required, which represents a considerable industrial advantage. Sponges also possess shape memory, and can therefore be repeatedly soaked and squeezed while still maintaining the same shape and structure characteristics, and requiring a single UV irradiation. The Applicant has demonstrated that this set of characteristics is associated with the use of a particular spacer, which makes the invention new and inventive compared with the prior art.
In particular, Example 8 and FIG. 8 illustrate the comparative data for the degree of swelling between hydrogels prepared according to Example 2 of said prior patent EP1519962, owned by the Applicant, and hydrogels prepared according to Example 15 of the present patent application. As the latter hydrogels absorb less water they are more compact, and crosslinking is therefore more efficient.